Research on the function and activity of estrogen receptors, the structure and their function has been the subject of many recent investigations. Estrogen receptors belong to a large family of structurally related ligand-inducible transcription factors, including steroid receptors, thyroid/retinoid receptors, vitamin D receptors known as nuclear receptors. While the true ligand for nuclear receptors have not been described, there are distinct small molecules that are able to bind to such receptors and trigger a cellular response.
Estrogens and estrogen receptor modulators bind to estrogen receptors, classified into two types; α and β, to form discrete molecular complexes that exert pleiotropic tissue-specific effects by modulating the expression of target genes. The ligand-bound estrogen receptor acts as a key transcription factor in various molecular pathways, and modulation of ER expression levels is important in determining cellular growth potential.
While both these types of receptors bind to estrogen, as well as other agonists and antagonists, the two receptors have distinctly different localization concentration within the body. Aside from some structural differences between the α and β types, when complex with estrogen, the two are shown to signal in opposite ways, with estrogen activating transcription in the presence of Estrogen Receptor α (ERα) and inhibiting transcription in the presence of Estrogen Receptor β (ERβ).
Estrogens regulate a large spectrum of neuronal functions, including pain perception. Recently, hotplate and formalin tests carried out in wild type (WT) and ERβ knockout (KO) mice demonstrated that pain inhibitory mechanisms and early tonic pain are modified by ERβ deficiency. Spooner, M. F. et al., Neuroscience 150, 675-680 (2007). Spooner et al. found that nociceptive responses are lower in ERβ KO female than in WT female mice during the interphase and early tonic phase II of the formalin test but not during acute and late tonic phases. This suggests that estrogen, through its actions on ERβ, dampens the efficacy of endogenous pain modulation mechanisms during the interphase and/or inflammation prosedd in the early phase II, triggering an increase in spinal nociceptive neuronal activity.
Further, ERb-131, a non-steroidal ERβ ligand was evaluated in several pain animal models involving nerve injury or sensitization. Piu, F. et al., European Journal of Pharmacology 590, 423-429 (2008); Piu, F. et al., European Journal of Pharmacology 592, 158-159 (2008). Using functional and binding assays, ERb-131 was characterized as a potent and selective ERβ agonist. In vivo, ERb-131 was devoid of estrogen receptor alpha activity as assessed in a rat uterotrophic assay. Also, ERb-131 alleviated tactile hyperalgesia induced by capsaicin, and reversed tactile allodynia caused by spinal nerve ligation and various chemical insults. Moreover, ERb-131 did not influence the pain threshold of normal healthy animals. In the chronic complete Freund's adjuvant model, ERb-131 resolved both inflammatory and hyperalgesic components of chronic pain. Thus, Piu et al. also demonstrates that ERβ agonism is a critical effector in attenuating a broad range of anti-nociceptive states.
Accordingly, there exists a need for new compounds that can selectively act on ERβ to assist in the treatment of pain. To date, none of the teachings of the prior art provide for a therapeutic 6-substituted 13-demethyl estradiol derivative that can be used for this type of treatment.